PROJECT SUMMARY Despite strong evidence that colorectal cancer (CRC) screening reduces mortality, rates of CRC screening, follow-up, and referral-to-care (herein referred to as ?CRC screening?) remain suboptimal in the US. In North Carolina (NC), underuse of screening contributes to particularly high CRC burden in certain regions. Community health centers (CHCs) play a critical role in providing CRC screening for these vulnerable populations. Yet, CRC screening rates in NC CHCs are well below the estimated national rate of 62%. Substantial efforts are needed to reach the national target of 80%. Because multiple patient-, provider-, and system-level factors contribute to low screening rates, multilevel interventions are needed to achieve screening targets. Accumulating evidence shows that interventions involving mailed screening outreach, practice-based screening in-reach (using patient navigators), and systematically improving colonoscopy access, all increase screening. However, in practice, CHCs face substantial resource limitations and lack the means to systematically implement a multi-level intervention of outreach, in-reach, and improved colonoscopy access for uninsured patients. Until a multi-level intervention is shown to be both effective and cost-effective from stakeholder perspectives, screening rates will remain low, leaving thousands of vulnerable patients at risk. We hypothesize that standardizing these interventions for CHCs at the state-level will yield cost-effective approaches to increasing screening. Our long-term goal is to reduce CRC burden and disparities through improved screening. Our objective here is to leverage our expertise in CRC screening intervention research, implementation science, stakeholder engagement, and modeling to achieve this goal for our state. Our central hypothesis is that a pragmatic trial assessing impacts and costs for combinations of these evidence-based interventions (EBIs) will yield one or more strategies that stakeholders find to be cost-effective and sustainable. The specific aims for our study are: Aim 1 (Planning and Exploratory Phase): Pilot test a multilevel intervention to increase CRC screening in vulnerable populations in three NC regions. In this phase, we will complete pilot studies needed for our signature trial, plan for implementation evaluation and sustainability, and develop a process for evaluating locally-developed innovative approaches for improving screening. Aim 2 (Implementation Phase): Building on Aim 1 findings, implement and evaluate multilevel CRC screening approaches in vulnerable populations in NC. In this phase, we will conduct our signature trial, assess implementation outcomes, evaluate the use of stakeholder-engaged modeling for sustaining and scaling the multilevel intervention, and select and evaluate locally-developed innovations for improving screening. This project is innovative in combining outreach and in-reach EBIs and in its use of stakeholder-engaged simulation modeling to inform sustainability. The proposed research is significant because it will have a substantial impact on CRC morbidity, mortality, and disparities in vulnerable communities.